Advancing cancer therapy: Developing antibody blockade targeting a novel immune checkpoint, LAIR1/CD305

PROJECT SUMMARY Our project focuses on overcoming inhibition by tumor-associated macrophages (TAMCs) within the tumor microenvironment (TME) to mitigate therapeutic resistance and achieve clinical responses. Leukocyte- associated Immunoglobulin-like Receptor 1 (LAIR1), predominantly found on M2-like TAM, is pivotal in their immunosuppressive function. Our research reveals LAIR1's involvement in a novel immunosuppressive LAIR1→FXIII-A→Collagen circuit, bolstering tumor-collagen deposition and shielding the tumor from immune attacks. Inhibiting LAIR1, either through knockout (LAIR1-/-) or antibody blockade (aLAIR1), augments peripheral and intratumoral memory CD8 T cell populations, induces a shift from M2-like TAM to M1 macrophage phenotype, and normalizes collagen and TME structure, facilitating effective tumor-T cell interactions and tumor suppression. Notably, LAIR1-/- or aLAIR1, alone or combined with CAR T cells, demonstrates an enhanced antitumor response even in PD-1 blockade-resistant models, underscoring LAIR1 inhibition as a promising strategy for novel cancer immunotherapy. Through these findings, we aim to advance therapeutic approaches targeting LAIR1 to improve outcomes for cancer patients by developing clinical grade aLAIR1. Our project endeavors are guided by a multidisciplinary team of experts, including scientists, clinicians, statisticians, and entrepreneurs. Aim 1 focuses on the in vitro validation of Hu-aLAIR1, involving the assessment of binding affinity, specificity, stability, and functional assay to measure blocking activity using a patient-matched tumor explant model. Milestones include the identification of a promising Hn-aLAIR1 candidate with LAIR1-specific binding activity and TAMC inhibition. Aim 2 involves conducting efficacy studies of Hu-aLAIR1 in tumor-bearing mice to evaluate pharmacokinetics, dose-response relationships, and antitumor efficacy, aiming to identify the maximum tolerated dose with optimal efficacy. Aim 3 encompasses pilot safety and toxicology testing, aiming to reach a No-Observed-Adverse-Effect Level (NOAEL) and complete the GLP-compliant protocol design for Phase II studies. Successfully fulfilling these objectives will pave the way for IND-enabling investigations and early-phase clinical trials, marking a crucial advancement in our journey toward impactful cancer therapy development. We recognize the importance of commercialization to ensure the translation of our research into tangible benefits for patients. Our project includes a comprehensive commercialization strategy that involves intellectual property inquiries, market analysis, and strategic potential partnerships with industry leaders in biotechnology and pharmaceuticals. We aim to accelerate the development and eventual commercialization of Hn-aLAIR1 as a promising cancer immunotherapy. Through these efforts, we strive to not only advance scientific knowledge but also to deliver innovative treatments to patients in need, ultimately making a meaningful impact in the fight against cancer.